The major objectives of the proposed research are twofold; first, to describe the properties of physiological pain modulating systems and, second, to apply recent advances in our understanding of these systems to develop a more rational approach to the management of pain. In the course of the research supported in previous years by this grant, we have studied over 1,000 dental postoperative pain patients. We have already developed a description of the time course of untreated pain and provided evidence that: the intensity of clinical pain is modulated by endogenous opioids (endorphins); endogenous opioids can mediate placebo-induced analgesia; and opiate-induced analgesia exhibits properties similar to placebo analgesia including a threshold pain intensity for activating analgesia systems. We propose to extend the period of time of our description of untreated pain in order to evaluate the role of the endorphin-mediated analgesia system (EMAS) in spontaneous fluctuations in pain intensity. This data will also be used to determine time-effect curves for commonly used analgesic agents. The role of the EMAS in determining the time course of narcotic-induced analgesia will be studied by comparing the time course of drugs in the plasma (pharmacokinetic studies) to the time course of analgesia following their administration. The role of serotonergic neurons in determining the time course of analgesia will be studied by evaluating the effect of a drug (amitripty-line), which blocks serotonin reuptake, on the time course of morphine-induced analgesia. Finally, we will use knowledge of the mechanisms of action of various analgesic agents to design more effective drug combinations. These studies should provide a more rational approach to the management of dental postoperative pain.